Abstract

Background

The tissue field generated by a magnetic susceptibility source, such as iron, and experienced by the surrounding water protons is linearly related to the MR signal phase, which can be measured with high precision in MRI. Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem. The clinical utility of QSM has been primarily applied to the brain and has shown utility across a vast range of neurodegenerative diseases.

Objectives

This presentation will provide the participants an opportunity to gain insight into the clinical potential of QSM, as it relates to the study of multiple sclerosis (MS).

Methods

QSM provides extensive insight into the early MS lesion, opening a new venue to investigate MS lesion inflammatory activity after blood brain barrier (BBB) closure. Chronic CNS inflammation in the MS lesion is maintained with pro-inflammatory microglia and macrophages (m/M), which have been demonstrated to be present at the rim of chronic active MS lesions and at the site of ongoing demyelination. The majority of the m/M found at the rim of chronic active multiple sclerosis lesions contain iron, and conversely iron-enriched microglia and macrophages are not found at the rim of remyelinated or shadow plaques. MRI with a gradient echo (GRE) sequence is sensitive to iron and has been utilized by many investigators to detect an iron rim in chronic active multiple sclerosis lesions. QSM provides quantification and localization of the magnetic sources, thus yielding benefits over other methods to identify and assess the paramagnetic rim present within this subset of chronic lesions.

Results

Utilizing PK11195-PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared on lesions lacking this rim. QSM rim+ lesions were also found to have more tissue injury, as measured by myelin water imaging. Building on this work, as well as histopathological validation studies, larger clinical studies are being are designed to establish the role of QSM rim+ lesions as a prognostic biomarker for disease activity and identify patients at risk for future disability. Similarly, the quantitative aspect of QSM provides the potential tool to assess treatment effect for drugs that may cross the BBB and target the innate immune response. Lastly, additional clinical applications of QSM for MS will be introduced and future directions will be discussed.

Conclusions

In conclusion, QSM is a validated quantitative imaging tool to explore the impact of chronic lesion pathology on clinical disability and to assess the potential therapeutic benefit of drugs targeting the innate immune response.

Abstract

Background

The tissue field generated by a magnetic susceptibility source, such as iron, and experienced by the surrounding water protons is linearly related to the MR signal phase, which can be measured with high precision in MRI. Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem. The clinical utility of QSM has been primarily applied to the brain and has shown utility across a vast range of neurodegenerative diseases.

Objectives

This presentation will provide the participants an opportunity to gain insight into the clinical potential of QSM, as it relates to the study of multiple sclerosis (MS).

Methods

QSM provides extensive insight into the early MS lesion, opening a new venue to investigate MS lesion inflammatory activity after blood brain barrier (BBB) closure. Chronic CNS inflammation in the MS lesion is maintained with pro-inflammatory microglia and macrophages (m/M), which have been demonstrated to be present at the rim of chronic active MS lesions and at the site of ongoing demyelination. The majority of the m/M found at the rim of chronic active multiple sclerosis lesions contain iron, and conversely iron-enriched microglia and macrophages are not found at the rim of remyelinated or shadow plaques. MRI with a gradient echo (GRE) sequence is sensitive to iron and has been utilized by many investigators to detect an iron rim in chronic active multiple sclerosis lesions. QSM provides quantification and localization of the magnetic sources, thus yielding benefits over other methods to identify and assess the paramagnetic rim present within this subset of chronic lesions.

Results

Utilizing PK11195-PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared on lesions lacking this rim. QSM rim+ lesions were also found to have more tissue injury, as measured by myelin water imaging. Building on this work, as well as histopathological validation studies, larger clinical studies are being are designed to establish the role of QSM rim+ lesions as a prognostic biomarker for disease activity and identify patients at risk for future disability. Similarly, the quantitative aspect of QSM provides the potential tool to assess treatment effect for drugs that may cross the BBB and target the innate immune response. Lastly, additional clinical applications of QSM for MS will be introduced and future directions will be discussed.

Conclusions

In conclusion, QSM is a validated quantitative imaging tool to explore the impact of chronic lesion pathology on clinical disability and to assess the potential therapeutic benefit of drugs targeting the innate immune response.

Abstract

Background

The tissue field generated by a magnetic susceptibility source, such as iron, and experienced by the surrounding water protons is linearly related to the MR signal phase, which can be measured with high precision in MRI. Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem. The clinical utility of QSM has been primarily applied to the brain and has shown utility across a vast range of neurodegenerative diseases.

Objectives

This presentation will provide the participants an opportunity to gain insight into the clinical potential of QSM, as it relates to the study of multiple sclerosis (MS).

Methods

QSM provides extensive insight into the early MS lesion, opening a new venue to investigate MS lesion inflammatory activity after blood brain barrier (BBB) closure. Chronic CNS inflammation in the MS lesion is maintained with pro-inflammatory microglia and macrophages (m/M), which have been demonstrated to be present at the rim of chronic active MS lesions and at the site of ongoing demyelination. The majority of the m/M found at the rim of chronic active multiple sclerosis lesions contain iron, and conversely iron-enriched microglia and macrophages are not found at the rim of remyelinated or shadow plaques. MRI with a gradient echo (GRE) sequence is sensitive to iron and has been utilized by many investigators to detect an iron rim in chronic active multiple sclerosis lesions. QSM provides quantification and localization of the magnetic sources, thus yielding benefits over other methods to identify and assess the paramagnetic rim present within this subset of chronic lesions.

Results

Utilizing PK11195-PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared on lesions lacking this rim. QSM rim+ lesions were also found to have more tissue injury, as measured by myelin water imaging. Building on this work, as well as histopathological validation studies, larger clinical studies are being are designed to establish the role of QSM rim+ lesions as a prognostic biomarker for disease activity and identify patients at risk for future disability. Similarly, the quantitative aspect of QSM provides the potential tool to assess treatment effect for drugs that may cross the BBB and target the innate immune response. Lastly, additional clinical applications of QSM for MS will be introduced and future directions will be discussed.

Conclusions

In conclusion, QSM is a validated quantitative imaging tool to explore the impact of chronic lesion pathology on clinical disability and to assess the potential therapeutic benefit of drugs targeting the innate immune response.

Background

Clinical heterogeneity among patients with multiple sclerosis (MS) may be driven by genetic and environmental influences that lead to distinctive MRI features.

Objectives

Our objective was to utilize a cluster analysis to determine the variability of quantitative MRI features among a cohort of MS patients and examine the ability of these imaging features to discriminate patients by clinical disability.

Methods

Ninety-six relapsing remitting MS patients and 7 patients with progressive MS underwent Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) sequence, for myelin water fraction (MWF) analysis, and conventional MRI for measures of lesion volume, cortical thickness and thalamic volume. An agglomerative hierarchical clustering algorithm was implemented using lesion level MRI features selected from a Principal Component Analysis (PCA). The final clusters were selected by implementing a comprehensive validation method based on several unsupervised statistical learning techniques. Matched cluster groups with statistically significant clinical covariates (i.e. age and disease duration) were analyzed based on propensity scores.

Results

A total of 1691 chronic MS lesions were identified among the 103 MS patients. Mean patient age was 44.4 (+/- 11.9) years, disease duration was 10.5 (+/- 8.3) years, and expanded disability status scale (EDSS) was 2.2 (+/- 2.0). PCA demonstrated lesion MWF and volume distributions characterized by 25^th, 50^th and 75^th percentiles account for 87% of the total variability. The hierarchical clustering confirmed two distinct patient clusters. The variables in order of importance were individual lesion median MWF, MWF 25^th, MWF 75^th, volume 75^th percentiles, median individual lesion volume, and total lesion volume (all p-values < 0.000001). Cortical thickness and thalamic volume were significant but less important on cluster discrimination. The clustering MRI features discriminated patients based upon EDSS, p=0.0016 at the time of MRI and maintained EDSS difference at five years (n=72), p=0.0016.

Conclusions

The size and extent of demyelination among individual lesions discriminated MS patients into two MRI lesion-based clusters and was associated with clinical disability. These results suggest an inherent difference among patients with regard to lesion pathology and repair.

Background

Hurst Exponent (HE) is a scalar measurement of long-term temporal memory of a time series. The HE has been found in previous studies to be an effective means of measuring the long-range temporal dependence of brain activity as measured by fMRI. We hypothesize that the HE can be associated with impairment in Multiple Sclerosis (MS), therefore can be an imaging biomarker of MS.

Objectives

The primary goal of the study is to assess how well HE measurements can distinguish MS patients from healthy controls (HC), as well as MS patients with impairment from those without impairment. The second objective was to identify which brain regions’ HE alterations are associated with impairment in MS.

Methods

Fifteen HC (age: 43.66±8.64, 53% female) and 76 MS patients (age:45.28±11.46 years, 65% female, disease duration:12.29±7.25 years) were included in our study; 23 had EDSS2 at study baseline. Logistic ridge regression (LR) was used to classify two groups: (1) HC vs MS patients and (2) MS patients with vs without impairment. The classification tasks were performed using HE measurements in 86 cortical and subcortical regions. Five-fold cross-validation was used to train, validate, and test the model, with 10 outer loop repetitions. Area Under ROC curve (AUC) over the folds was used to assess classification performance.

Results

HE was found to be significantly higher in the non-impaired group compared to the impaired group in the right superior frontal gyrus (corrected p-value=0.025). The classification of HC vs MS had an AUC of 0.65 (IQR:0.18), while the task of classifying MS patients by impairment level had an AUC of 0.63 (IQR: 0.12). For the classification of HC vs MS, the regions that were the most predictive were in deep gray matter. Lower HE in the left amygdala, left thalamus and left putamen, and higher HE in the left hippocampus was associated with MS. For the classification of impairment level in MS, deep gray matter regions were also important, as were HE in the frontal lobe. Lower HE in the left caudate, right and left amygdala, and left superior frontal and higher HE in the right ventral DC were associated with more impairment in MS.

Conclusions

HE was found to be moderately discriminative between HC and MS and within impairment levels in MS. HE in subcortical and superior frontal regions were found to be important biomarkers of impairment severity in MS, as well as in distinguishing MS patients from HC. Further research is necessary to identify the mechanism driving these differences.

Background

Chronic active multiple sclerosis (MS) lesions, characterized by a hyperintense rim (rim+) on quantitative susceptibility mapping (QSM), have been shown to contain iron-enriched, activated microglia and macrophages. QSM is a potential biomarker to monitor treatments directed toward the CNS inflammation. Studies have suggested that dimethyl fumarate (DMF) may reduce the pro-inflammatory innate immune response in the CNS. A comparison to other disease modifying therapies (DMTs) is warranted to evaluate this potential benefit.

Objectives

To determine if dimethyl fumarate (DMF) reduces the iron load, as measured on QSM, in chronic active MS lesions at a greater rate than glatiramer acetate (GA) treatment.

Methods

Sixty-one patients (41 female, 20 male, mean age: 42.1 years +/- 10.9 and EDSS 0.82 +/- 1.2), were considered for this analysis. Fifty-six patients had relapsing-remitting MS and 5 had clinically-isolated syndrome; 37 patients were treated with DMF and 24 with GA. The two treatment groups had similar baseline clinical characteristics; however, DMF patients had less time on treatment as compared to GA (3.86 +/- 1.75 years vs 5.99 +/- 2.67 years, p<0.001). Patients had a QSM scan prior to treatment and a minimum of two on-treatment QSM MRIs. Lesions were classified as rim+ or rim- negative based upon a review of two independent reviewers. To compare longitudinal QSM change in the rim+ lesions among treatment groups, a linear mixed effects model was utilized.

Results

At baseline, patients treated with GA had more QSM rim+ lesions (9.4%) as compared to those starting DMF (4.5%), p=0.0004, however the number of patients having at least one rim+ lesion was similar (16 vs 18 patients) among the treatment groups. DMF patients with rim+ lesions had a longer disease duration as compared to rim+ GA patients (8.15 +/- 6.82 vs 3.55 +/- 4.85 years, p= 0.032). In the subset of patients with QSM rim+ lesions, there was a significantly larger decrease in susceptibility in rim+ lesions with DMF treatment as compared to GA, p< 0.0009. There was minimal reduction of susceptibility in rim- lesions, which was similar among treatment groups; all patients (p=0.92) and QSM rim+ only patients (p=0.11).

Conclusions

This study suggests that DMF reduces the iron load in rim+ MS lesions at a greater rate than GA. These results support QSM to evaluate the effectiveness of various DMTs on the CNS innate immune response in chronic active MS lesions.

Background

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a well-established neuropsychological battery to evaluate cognitive changes in patients with Multiple Sclerosis (MS). FreeSurfer has been used to assess neuroanatomical features, including cortical thickness and subcortical volume, as correlates of disease activity. The evaluation of cognitive performance, when combined with FreeSurfer analysis, may offer unique cross-sectional insight into the natural history of MS and the ways in which neurodegeneration interacts with cognition across different stages of disease.

Objectives

This study aims to take a cross-sectional view of a large MS patient cohort and study the relationship between cortical/subcortical measurements and cognitive function across various domains. Its objective is to compare the differences in cortical thickness and subcortical volume in subjects who are cognitively impaired and cognitively unimpaired.

Methods

163 patients with MS underwent both T1-weighted magnetic resonance imaging (MRI) and formal BICAMS testing within three months of one another. FreeSurfer was then used to analyze imaging data. BICAMS includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT). Impairment was based upon published age-matched normative data. Patients had a mean disease duration of 10.5 +/- 7.3 years; mean Expanded Disability Status Scale (EDSS) of 1.3 +/- 1.6; mean age of 42.9 +/- 10.5 years. Multivariate regression analysis was used to compare cortical thickness and subcortical volume in impaired vs.unimpaired subjects.

Results

31, 15 and 38 patients were found to be impaired on SDMT, CVLT, and BVMT testing, respectively. Significant differences were found in multiple subcortical regions among impaired and unimpaired on SDMT (Thalamus; p=0.01) and BVMT (Left/Right Accumbens; p=0.001, p=0.02; Caudate; p=<0.001; Left Cerebellum; p=0.02; Left/Right Hippocampus; p=0.004, p=0.02; Left Pallidum; p=0.01; Left/Right Putamen; p=0.02, p=0.004; Right Amygdala; p=0.02; Right Thalamus; p=0.004). Impairment on SDMT was associated with differences in caudal anterior cingulate cortex (p= 0.001) and entorhinal cortex (p=0.003) and BVMT impairment was associated with thinning in temporal lobe regions (Right Bank of Superior Temporal Lobe; p=0.008; Right Fusiform; p=0.02). SDMT, CVLT, BVMT were all associated with differences in various occipital lobe regions. No significant differences were found when looking at the four anatomic lobes in their entirety.

Conclusions

Our results show associations between impaired performance on certain neuropsychological tests and regional cortical thinning and subcortical volume loss in what is the largest known cohort to date. These findings could shed light on unique and overlapping neuroanatomical substrates underlying different cognitive processes in MS.